Browse > Article
http://dx.doi.org/10.4110/in.2015.15.4.191

Immune-mediated Liver Injury in Hepatitis B Virus Infection  

Oh, In Soo (Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST)
Park, Su-Hyung (Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST)
Publication Information
IMMUNE NETWORK / v.15, no.4, 2015 , pp. 191-198 More about this Journal
Abstract
Hepatitis B virus (HBV) is responsible for approximately 350 million chronic infections worldwide and is a leading cause of broad-spectrum liver diseases such as hepatitis, cirrhosis and liver cancer. Although it has been well established that adaptive immunity plays a critical role in viral clearance, the pathogenetic mechanisms that cause liver damage during acute and chronic HBV infection remain largely known. This review describes our current knowledge of the immune-mediated pathogenesis of HBV infection and the role of immune cells in the liver injury during hepatitis B.
Keywords
Hepatitis B Virus; Pathogenesis; Immune response;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Park, S. H., and B. Rehermann. 2014. Immune responses to HCV and other hepatitis viruses. Immunity 40: 13-24.   DOI
2 Chisari, F. V., M. Isogawa, and S. F. Wieland. 2010. Pathogenesis of hepatitis B virus infection. Pathol. Biol. (Paris) 58: 258-266.   DOI
3 Ocama, P., C. K. Opio, and W. M. Lee. 2005. Hepatitis B virus infection: current status. Am. J. Med. 118: 1413.
4 Guidotti, L. G., and F. V. Chisari. 2006. Immunobiology and pathogenesis of viral hepatitis. Annu. Rev. Pathol. 1: 23-61.   DOI
5 Rehermann, B., P. Fowler, J. Sidney, J. Person, A. Redeker, M. Brown, B. Moss, A. Sette, and F. V. Chisari. 1995. The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis. J. Exp. Med. 181: 1047-1058.   DOI
6 Baumert, T. F., R. Thimme, and W. F. von. 2007. Pathogenesis of hepatitis B virus infection. World J. Gastroenterol. 13: 82-90.   DOI
7 Wieland, S., R. Thimme, R. H. Purcell, and F. V. Chisari. 2004. Genomic analysis of the host response to hepatitis B virus infection. Proc. Natl. Acad. Sci. U. S. A. 101: 6669-6674.   DOI
8 Ando, K., L. G. Guidotti, S. Wirth, T. Ishikawa, G. Missale, T. Moriyama, R. D. Schreiber, H. J. Schlicht, S. N. Huang, and F. V. Chisari. 1994. Class I-restricted cytotoxic T lymphocytes are directly cytopathic for their target cells in vivo. J. Immunol. 152: 3245-3253.
9 Kondo, T., T. Suda, H. Fukuyama, M. Adachi, and S. Nagata. 1997. Essential roles of the Fas ligand in the development of hepatitis. Nat. Med. 3: 409-413.   DOI
10 Galle, P. R., W. J. Hofmann, H. Walczak, H. Schaller, G. Otto, W. Stremmel, P. H. Krammer, and L. Runkel. 1995. Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J. Exp. Med. 182: 1223-1230.   DOI
11 Kakimi, K., T. E. Lane, S. Wieland, V. C. Asensio, I. L. Campbell, F. V. Chisari, and L. G. Guidotti. 2001. Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J. Exp. Med. 194: 1755-1766.   DOI
12 Guidotti, L. G., R. Rochford, J. Chung, M. Shapiro, R. Purcell, and F. V. Chisari. 1999. Viral clearance without destruction of infected cells during acute HBV infection. Science 284: 825-829.   DOI
13 Sells, M. A., M. L. Chen, and G. Acs. 1987. Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA. Proc. Natl. Acad. Sci. U. S. A. 84: 1005-1009.   DOI
14 Quasdorff, M., M. Hosel, M. Odenthal, U. Zedler, F. Bohne, P. Gripon, H. P. Dienes, U. Drebber, D. Stippel, T. Goeser, and U. Protzer. 2008. A concerted action of HNF4alpha and HNF1alpha links hepatitis B virus replication to hepatocyte differentiation. Cell. Microbiol. 10: 1478-1490.   DOI
15 Schulze-Bergkamen, H., A. Untergasser, A. Dax, H. Vogel, P. Buchler, E. Klar, T. Lehnert, H. Friess, M. W. Buchler, M. Kirschfink, W. Stremmel, P. H. Krammer, M. Muller, and U. Protzer. 2003. Primary human hepatocytes--a valuable tool for investigation of apoptosis and hepatitis B virus infection. J. Hepatol. 38: 736-744.
16 Guidotti, L. G., B. Matzke, H. Schaller, and F. V. Chisari. 1995. High-level hepatitis B virus replication in transgenic mice. J. Virol. 69: 6158-6169.
17 McMahon, B. J. 2009. The natural history of chronic hepatitis B virus infection. Hepatology 49: S45-S55.   DOI
18 Chisari, F. V., and C. Ferrari. 1995. Hepatitis B virus immunopathogenesis. Annu. Rev. Immunol. 13: 29-60.   DOI
19 Ferrari, C., G. Missale, C. Boni, and S. Urbani. 2003. Immunopathogenesis of hepatitis B. J. Hepatol. 39 Suppl 1: S36-S42.   DOI
20 Ganem, D., and A. M. Prince. 2004. Hepatitis B virus infection--natural history and clinical consequences. N. Engl. J. Med. 350: 1118-1129.   DOI
21 Sitia, G., M. Isogawa, K. Kakimi, S. F. Wieland, F. V. Chisari, and L. G. Guidotti. 2002. Depletion of neutrophils blocks the recruitment of antigen-nonspecific cells into the liver without affecting the antiviral activity of hepatitis B virus-specific cytotoxic T lymphocytes. Proc. Natl. Acad. Sci. U. S. A. 99: 13717-13722.   DOI
22 Iannacone, M., G. Sitia, I. Narvaiza, Z. M. Ruggeri, and L. G. Guidotti. 2007. Antiplatelet drug therapy moderates immune-mediated liver disease and inhibits viral clearance in mice infected with a replication-deficient adenovirus. Clin. Vaccine Immunol. 14: 1532-1535.   DOI
23 Lang, P. A., C. Contaldo, P. Georgiev, A. M. El-Badry, M. Recher, M. Kurrer, L. Cervantes-Barragan, B. Ludewig, T. Calzascia, B. Bolinger, D. Merkler, B. Odermatt, M. Bader, R. Graf, P. A. Clavien, A. N. Hegazy, M. Lohning, N. L. Harris, P. S. Ohashi, H. Hengartner, R. M. Zinkernagel, and K. S. Lang. 2008. Aggravation of viral hepatitis by platelet-derived serotonin. Nat. Med. 14: 756-761.   DOI
24 Tsui, L. V., L. G. Guidotti, T. Ishikawa, and F. V. Chisari. 1995. Posttranscriptional clearance of hepatitis B virus RNA by cytotoxic T lymphocyte-activated hepatocytes. Proc. Natl. Acad. Sci. U. S. A. 92: 12398-12402.   DOI
25 Urbani, S., C. Boni, B. Amadei, P. Fisicaro, S. Cerioni, M. A. Valli, G. Missale, and C. Ferrari. 2005. Acute phase HBV-specific T cell responses associated with HBV persistence after HBV/HCV coinfection. Hepatology 41: 826-831.   DOI
26 Barnaba, V., A. Franco, A. Alberti, C. Balsano, R. Benvenuto, and F. Balsano. 1989. Recognition of hepatitis B virus envelope proteins by liver-infiltrating T lymphocytes in chronic HBV infection. J. Immunol. 143: 2650-2655.
27 Burton, D. R., R. A. Williamson, and P. W. Parren. 2000. Antibody and virus: binding and neutralization. Virology 270: 1-3.   DOI
28 Servet-Delprat, C., P. O. Vidalain, O. Azocar, D. F. Le, A. Fischer, and C. Rabourdin-Combe. 2000. Consequences of Fas-mediated human dendritic cell apoptosis induced by measles virus. J. Virol. 74: 4387-4393.   DOI
29 Su, F., C. N. Theodosis, and R. J. Schneider. 2001. Role of NF-kappaB and myc proteins in apoptosis induced by hepatitis B virus HBx protein. J. Virol. 75: 215-225.   DOI
30 Terradillos, O., T. Pollicino, H. Lecoeur, M. Tripodi, M. L. Gougeon, P. Tiollais, and M. A. Buendia. 1998. p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro. Oncogene 17: 2115-2123.   DOI
31 Kim, K. H., and B. L. Seong. 2003. Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal. EMBO J. 22: 2104-2116.   DOI
32 Miao, J., G. G. Chen, S. Y. Chun, and P. P. Lai. 2006. Hepatitis B virus X protein induces apoptosis in hepatoma cells through inhibiting Bcl-xL expression. Cancer Lett. 236: 115-124.   DOI
33 Brenner, C., L. Galluzzi, O. Kepp, and G. Kroemer. 2013. Decoding cell death signals in liver inflammation. J. Hepatol. 59: 583-594.   DOI
34 Kroemer, G., L. Galluzzi, and C. Brenner. 2007. Mitochondrial membrane permeabilization in cell death. Physiol. Rev. 87: 99-163.   DOI
35 Kirby, J., K. A. Levin, and J. Inchley. 2013. Socio-environmental influences on physical activity among young people: a qualitative study. Health Educ. Res. 28: 954-969.   DOI
36 Krtolica, A., S. Parrinello, S. Lockett, P. Y. Desprez, and J. Campisi. 2001. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl. Acad. Sci. U. S. A. 98: 12072-12077.   DOI
37 Schilling, R., S. Ijaz, M. Davidoff, J. Y. Lee, S. Locarnini, R. Williams, and N. V. Naoumov. 2003. Endocytosis of hepatitis B immune globulin into hepatocytes inhibits the secretion of hepatitis B virus surface antigen and virions. J. Virol. 77: 8882-8892.   DOI
38 Rehermann, B., C. Ferrari, C. Pasquinelli, and F. V. Chisari. 1996. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat. Med. 2: 1104-1108.   DOI
39 Moss, B., G. L. Smith, J. L. Gerin, and R. H. Purcell. 1984. Live recombinant vaccinia virus protects chimpanzees against hepatitis B. Nature 311: 67-69.   DOI
40 Cooper, N. R. and G. R. Nemerow. 1983. Complement, viruses, and virus-infected cells. Springer Semin. Immunopathol. 6: 327-347.   DOI
41 Acs, G., M. A. Sells, R. H. Purcell, P. Price, R. Engle, M. Shapiro, and H. Popper. 1987. Hepatitis B virus produced by transfected Hep G2 cells causes hepatitis in chimpanzees. Proc. Natl. Acad. Sci. U. S. A. 84: 4641-4644.   DOI
42 Diao, J., A. A. Khine, F. Sarangi, E. Hsu, C. Iorio, L. A. Tibbles, J. R. Woodgett, J. Penninger, and C. D. Richardson. 2001. X protein of hepatitis B virus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway. J. Biol. Chem. 276: 8328-8340.   DOI
43 Shih, W. L., M. L. Kuo, S. E. Chuang, A. L. Cheng, and S. L. Doong. 2000. Hepatitis B virus X protein inhibits transforming growth factor-beta -induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway. J. Biol. Chem. 275: 25858-25864.   DOI
44 Marusawa, H., S. Matsuzawa, K. Welsh, H. Zou, R. Armstrong, I. Tamm, and J. C. Reed. 2003. HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J. 22: 2729-2740.   DOI
45 Lee, Y. I., S. Kang-Park, S. I. Do, and Y. I. Lee. 2001. The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J. Biol. Chem. 276: 16969-16977.   DOI
46 Elmore, L. W., A. R. Hancock, S. F. Chang, X. W. Wang, S. Chang, C. P. Callahan, D. A. Geller, H. Will, and C. C. Harris. 1997. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc. Natl. Acad. Sci. U. S. A. 94: 14707-14712.   DOI
47 Huo, T. I., X. W. Wang, M. Forgues, C. G. Wu, E. A. Spillare, C. Giannini, C. Brechot, and C. C. Harris. 2001. Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis. Oncogene 20: 3620-3628.   DOI
48 Assrir, N., P. Soussan, D. Kremsdorf, and J. M. Rossignol. 2010. Role of the hepatitis B virus proteins in pro- and anti-apoptotic processes. Front. Biosci. (Landmark Ed.) 15: 12-24.   DOI
49 Su, F., and R. J. Schneider. 1997. Hepatitis B virus HBx protein sensitizes cells to apoptotic killing by tumor necrosis factor alpha. Proc. Natl. Acad. Sci. U. S. A. 94: 8744-8749.   DOI
50 Lindros, K. O., T. Oinonen, J. Issakainen, P. Nagy, and S. S. Thorgeirsson. 1997. Zonal distribution of transcripts of four hepatic transcription factors in the mature rat liver. Cell Biol. Toxicol. 13: 257-262.   DOI
51 Locaputo, S., T. L. Carrick, and J. A. Bezerra. 1999. Zonal regulation of gene expression during liver regeneration of urokinase transgenic mice. Hepatology 29: 1106-1113.   DOI
52 Iannacone, M., G. Sitia, M. Isogawa, P. Marchese, M. G. Castro, P. R. Lowenstein, F. V. Chisari, Z. M. Ruggeri, and L. G. Guidotti. 2005. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat. Med. 11: 1167-1169.   DOI
53 Norris, S., C. Collins, D. G. Doherty, F. Smith, G. McEntee, O. Traynor, N. Nolan, J. Hegarty, and C. O'Farrelly. 1998. Resident human hepatic lymphocytes are phenotypically different from circulating lymphocytes. J. Hepatol. 28: 84-90.
54 Ramadori, G., and B. Saile. 2004. Inflammation, damage repair, immune cells, and liver fibrosis: specific or nonspecific, this is the question. Gastroenterology 127: 997-1000.   DOI
55 Bonorino, P., M. Ramzan, X. Camous, T. Dufeu-Duchesne, M. A. Thelu, N. Sturm, A. Dariz, C. Guillermet, M. Pernollet, J. P. Zarski, P. N. Marche, V. Leroy, and E. Jouvin-Marche. 2009. Fine characterization of intrahepatic NK cells expressing natural killer receptors in chronic hepatitis B and C. J. Hepatol. 51: 458-467.   DOI
56 Oliviero, B., S. Varchetta, E. Paudice, G. Michelone, M. Zaramella, D. Mavilio, F. F. De, S. Bruno, and M. U. Mondelli. 2009. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology 137: 1151-1160.   DOI
57 Zhao, J., Y. Li, L. Jin, S. Zhang, R. Fan, Y. Sun, C. Zhou, Q. Shang, W. Li, Z. Zhang, and F. S. Wang. 2012. Natural killer cells are characterized by the concomitantly increased interferongamma and cytotoxicity in acute resolved hepatitis B patients. PLoS One 7: e49135.   DOI
58 Varchetta, S., D. Mele, S. Mantovani, B. Oliviero, E. Cremonesi, S. Ludovisi, G. Michelone, M. Alessiani, R. Rosati, M. Montorsi, and M. U. Mondelli. 2012. Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection. Hepatology 56: 841-849.   DOI
59 Nattermann, J., G. Feldmann, G. Ahlenstiel, B. Langhans, T. Sauerbruch, and U. Spengler. 2006. Surface expression and cytolytic function of natural killer cell receptors is altered in chronic hepatitis C. Gut 55: 869-877.   DOI
60 Guidotti, L. G., T. Ishikawa, M. V. Hobbs, B. Matzke, R. Schreiber, and F. V. Chisari. 1996. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 4: 25-36.   DOI
61 Dunn, C., M. Brunetto, G. Reynolds, T. Christophides, P. T. Kennedy, P. Lampertico, A. Das, A. R. Lopes, P. Borrow, K. Williams, E. Humphreys, S. Afford, D. H. Adams, A. Bertoletti, and M. K. Maini. 2007. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J. Exp. Med. 204: 667-680.   DOI
62 Zhang, Z., S. Zhang, Z. Zou, J. Shi, J. Zhao, R. Fan, E. Qin, B. Li, Z. Li, X. Xu, J. Fu, J. Zhang, B. Gao, Z. Tian, and F. S. Wang. 2011. Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients. Hepatology 53: 73-85.   DOI
63 Arababadi, M. K., A. A. Pourfathollah, A. Jafarzadeh, and G. Hassanshahi. 2010. Serum Levels of IL-10 and IL-17A in Occult HBV-Infected South-East Iranian Patients. Hepat. Mon. 10: 31-35.
64 Arababadi, M. K., A. A. Pourfathollah, A. Jafarzadeh, G. Hassanshahi, S. Daneshmandi, A. Shamsizadeh, and D. Kennedy. 2011. Non-association of IL-12 +1188 and IFN-gamma +874 polymorphisms with cytokines serum level in occult HBV infected patients. Saudi. J. Gastroenterol. 17: 30-35.   DOI
65 Khorramdelazad, H., G. Hassanshahi, A. B. Nasiri, and A. M. Kazemi. 2012. High Serum Levels of TGF-beta in Iranians With Chronic HBV Infection. Hepat. Mon. 12: e7581.
66 Wieland, S. F., and F. V. Chisari. 2005. Stealth and cunning: hepatitis B and hepatitis C viruses. J. Virol. 79: 9369-9380.   DOI
67 Bigger, C. B., K. M. Brasky, and R. E. Lanford. 2001. DNA microarray analysis of chimpanzee liver during acute resolving hepatitis C virus infection. J. Virol. 75: 7059-7066.   DOI
68 Su, A. I., J. P. Pezacki, L. Wodicka, A. D. Brideau, L. Supekova, R. Thimme, S. Wieland, J. Bukh, R. H. Purcell, P. G. Schultz, and F. V. Chisari. 2002. Genomic analysis of the host response to hepatitis C virus infection. Proc. Natl. Acad. Sci. U. S. A. 99: 15669-15674.   DOI
69 Seeger, C., and W. S. Mason. 2000. Hepatitis B virus biology. Microbiol. Mol. Biol. Rev. 64: 51-68.   DOI
70 Missale, G., A. Redeker, J. Person, P. Fowler, S. Guilhot, H. J. Schlicht, C. Ferrari, and F. V. Chisari. 1993. HLA-A31- and HLAAw68-restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis. J. Exp. Med. 177: 751-762.   DOI
71 Rehermann, B., and M. Nascimbeni. 2005. Immunology of hepatitis B virus and hepatitis C virus infection. Nat. Rev. Immunol. 5: 215-229.   DOI
72 Maini, M. K., C. Boni, C. K. Lee, J. R. Larrubia, S. Reignat, G. S. Ogg, A. S. King, J. Herberg, R. Gilson, A. Alisa, R. Williams, D. Vergani, N. V. Naoumov, C. Ferrari, and A. Bertoletti. 2000. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J. Exp. Med. 191: 1269-1280.   DOI
73 Shirakata, Y., and K. Koike. 2003. Hepatitis B virus X protein induces cell death by causing loss of mitochondrial membrane potential. J. Biol. Chem. 278: 22071-22078.   DOI
74 Pan, J., L. X. Duan, B. S. Sun, and M. A. Feitelson. 2001. Hepatitis B virus X protein protects against anti-Fas-mediated apoptosis in human liver cells by inducing NF-kappa B. J. Gen. Virol. 82: 171-182.   DOI
75 Arzberger, S., M. Hosel, and U. Protzer. 2010. Apoptosis of hepatitis B virus-infected hepatocytes prevents release of infectious virus. J. Virol. 84: 11994-12001.   DOI
76 Sitia, G., R. Aiolfi, L. P. Di, M. Mainetti, A. Fiocchi, F. Mingozzi, A. Esposito, Z. M. Ruggeri, F. V. Chisari, M. Iannacone, and L. G. Guidotti. 2012. Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc. Natl. Acad. Sci. U. S. A. 109: E2165-E2172.   DOI
77 Biron, C. A., K. B. Nguyen, G. C. Pien, L. P. Cousens, and T. P. Salazar-Mather. 1999. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17: 189-220.   DOI
78 Bertoletti, A., C. Ferrari, F. Fiaccadori, A. Penna, R. Margolskee, H. J. Schlicht, P. Fowler, S. Guilhot, and F. V. Chisari. 1991. HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. Proc. Natl. Acad. Sci. U. S. A. 88: 10445-10449.   DOI
79 Sitia, G., M. Isogawa, M. Iannacone, I. L. Campbell, F. V. Chisari, and L. G. Guidotti. 2004. MMPs are required for recruitment of antigen-nonspecific mononuclear cells into the liver by CTLs. J. Clin. Invest. 113: 1158-1167.   DOI
80 Shouval, D., and D. Samuel. 2000. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review. Hepatology 32: 1189-1195.   DOI
81 Thimme, R., S. Wieland, C. Steiger, J. Ghrayeb, K. A. Reimann, R. H. Purcell, and F. V. Chisari. 2003. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J. Virol. 77: 68-76.   DOI